β-arrestin mediates β1-adrenergic receptor-epidermal growth factor receptor interaction and downstream signaling

Douglas G. Tilley, Il Man Kim, Priyesh A. Patel, Jonathan D. Violin, Howard A. Rockman

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

β1-Adrenergic receptor (α1AR) stimulation confers cardio-protection via β-arrestin-dependent transactivation of epidermal growth factor receptors (EGFRs), however, the precise mechanism for this salutary process is unknown. We tested the hypothesis that the β1AR and EGFR form a complex that differentially directs intracellular signaling pathways. β1AR stimulation and EGF ligand can each induce equivalent EGFR phosphorylation, internalization, and downstream activation of ERK1/2, but only EGF ligand causes translocation of activated ERK to the nucleus, whereas β1AR-stimulated/EGFR-transactivated ERK is restricted to the cytoplasm. β1AR and EGFR are shown to interact as a receptor complex both in cell culture and endogenously in human heart, an interaction that is selective and undergoes dynamic regulation by ligand stimulation. Although catecholamine stimulation mediates the retention of β1AR-EGFR interaction throughout receptor internalization, direct EGF ligand stimulation initiates the internalization of EGFR alone. Continued interaction of β1AR with EGFR following activation is dependent upon C-terminal tail GRK phosphorylation sites of the β1AR and recruitment of β-arrestin. These data reveal a new signaling paradigm in which β-arrestin is required for the maintenance of a β1AR-EGFR interaction that can direct cytosolic targeting of ERK in response to catecholamine stimulation.

Original languageEnglish (US)
Pages (from-to)20375-20386
Number of pages12
JournalJournal of Biological Chemistry
Volume284
Issue number30
DOIs
StatePublished - Jul 24 2009
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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